Diagn Mol Pathol  2001 Jun;10(2):116-22 

beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite
instability in endometrioid ovarian carcinomas and synchronous endometrial
carcinomas.

Moreno-Bueno G, Gamallo C, Perez-Gallego L, de Mora JC, Suarez A, Palacios J.

Programa de Patologia Molecular, Centro Nacional de Investigaciones Oncologicas
(CNIO), Madrid, Spain.

beta-Catenin gene mutations and microsatellite instability (MI) have been
reported in endometrioid ovarian carcinomas. In colon but not endometrial
cancer, beta-catenin gene mutations are associated with a replication error
phenotype and MI. In this study the authors investigate whether beta-catenin
mutations and MI are two independent oncogenic pathways in endometrioid ovarian
carcinomas. They also evaluate the usefulness of these molecular markers in
determining the primary origin of simultaneous tumors in the ovary and
endometrium. This study was performed on 26 patients diagnosed with primary
endometrioid ovarian carcinoma, five of whom also had pathologically diagnosed
primary synchronous endometrioid endometrial carcinoma. Immunohistochemical and
molecular analyses indicated that there were 25 primary ovarian tumors with four
primary synchronous endometrial cancers and one ovarian metastasis of a primary
endometrial carcinoma. All studies were performed on formalin-fixed,
paraffin-embedded tissue samples. The beta-catenin expression pattern (nuclear
vs. membranous) was analyzed immunohistochemically. Mutations in exon 3 of the
beta-catenin gene were studied by polymerase chain reaction, single-strand
conformational polymorphism, and direct sequencing. MI status was established by
studying BAT-26 and BAT-25 mononucleotide repeats. In the group with 21 single
ovarian tumors, 18 (85%) had beta-catenin nuclear expression, eight (38%) had
beta-catenin gene mutations (always associated with beta-catenin nuclear
expression), and four (19%) had MI. Only one case (5%) had both beta-catenin
gene mutations and MI. The mutations affected one of the serine/threonine
residues targeted for phosphorylation by glycogen synthase kinase-3beta or
adjacent residues. At codon 32, a GAC-to-TAC (D32Y) change was found; at codon
33, two TCT-to-TGT (S33C) changes were found; at codon 37, three TCT-to-TTT
(S37F) changes and one TCT-to-TGT (S37C) change were found; and, lastly, one
ACC-to-GCC change at codon 41 (T41A) was detected. Four of the 25 endometrioid
ovarian carcinomas (16%) had an associated synchronous endometrial carcinoma.
There was a higher percentage of beta-catenin mutations (n = 3, 75%) in
synchronous ovarian carcinomas than in single ones, although with a similar
percentage of MI (n = 1, 25%). beta-catenin mutations were S37C in two cases and
D32G in one. One of the four endometrial carcinomas showed an S33C beta-catenin
mutation, and two carcinomas had MI. None of the four tumors had both
beta-catenin gene mutation and MI. beta-catenin gene mutations were always
associated with a nuclear beta-catenin expression pattern, whereas MI was
associated with a membranous pattern. In one patient both the ovarian and the
endometrial carcinomas had beta-catenin gene mutations, in another patient both
tumors showed MI, whereas in the remaining two patients the ovarian carcinomas
showed beta-catenin gene mutations and the endometrial carcinomas showed MI. To
summarize, the results of this study suggest that beta-catenin mutations and MI
could represent two independent pathways in endometrioid ovarian carcinomas
because they occur simultaneously very infrequently (in 5% of these cases).
beta-catenin mutations are always associated with a nuclear beta-catenin
expression pattern, whereas cases with a replication error -plus phenotype
showed no abnormal beta-catenin subcellular localization. The study of the
beta-catenin expression pattern, beta-catenin mutations, and MI, together with
conventional clinicopathologic findings, could aid in distinguishing between the
metastatic or independent origin of simultaneous endometrioid ovarian and
endometrial carcinomas. Tumors with identical immunohistochemical and molecular
features should therefore be considered to have a common origin.

PMID: 11385321 [PubMed - indexed for MEDLINE]